Published online Sep 20, 2024. doi: 10.5493/wjem.v14.i3.96269
Revised: May 26, 2024
Accepted: June 14, 2024
Published online: September 20, 2024
Processing time: 120 Days and 0.4 Hours
Esophageal squamous cell carcinoma (ESCC) is a substantial global health bur
Core Tip: Esophageal squamous cell carcinoma (ESCC) utilizes immune escape mechanisms, including major histocompatibility complex downregulation and immune checkpoint manipulation, enhancing tumor progression. The aryl hydrocarbon receptor (AhR), crucial in health and disease, significantly influences ESCC development and immune evasion through carcinogenic pathways. AhR activation triggers proliferation, inhibits apoptosis, and induces epithelial-mesenchymal transition. Moreover, AhR suppresses effector T cells and enrolls immunosuppressive myeloid cells. Therapeutic AhR targeting with AhR ligands showed promise in inhibiting tumor growth, controlling the immune microenvironment, and enhancing treatment efficacy. Combining AhR-targeted therapies with conventional treatments or dietary interventions has the potential to improve ESCC patient outcomes.
- Citation: Rahmati M, Moghtaderi H, Mohammadi S, Al-Harrasi A. Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma: From immune modulation to therapeutic opportunities. World J Exp Med 2024; 14(3): 96269
- URL: https://www.wjgnet.com/2220-315x/full/v14/i3/96269.htm
- DOI: https://dx.doi.org/10.5493/wjem.v14.i3.96269
Esophageal squamous cell carcinoma (ESCC), a severe malignancy of the esophagus, shows a significant global health burden (ESCC is the eighth most common cancer globally)[1]. It shows a notable geographical variation, with particularly high incidence rates in East Asia, Central Asia, and certain regions of Africa[2].
ESCC emerges through a multistep process involving progressive genetic and molecular alterations within the esophageal epithelium[3]. Chronic exposure to established carcinogens, such as tobacco smoke and excessive alcohol consumption, triggers cellular damage and initiates a cascade of events leading to uncontrolled proliferation and malig
Despite advancements in treatment procedures, ESCC prognosis is still poor, emphasizing the need for a better un
ESCC development is counterbalanced by the host immune system, which employs a two-edged plan for immune surveillance, including innate and adaptive immunity[8]. The ability of cancer cells to evade the detection of immune system and elimination is a hallmark of tumor progression[9]. In ESCC, the immune escape demonstrates through a sophisticated connection of various mechanisms utilized by tumor cells to create a microenvironment that protects them from immune attack[10].
To escape the strong immune surveillance system, ESCC cells organize a multi-dimensional immune escape program (Figure 1). One of the key mechanisms includes downregulation of major histocompatibility complex (MHC) molecules on the cell surface[11]. MHC molecules function as antigen presentation platforms, allowing T cells to recognize and eliminate foreign or abnormal cells. By reducing MHC expression, ESCC cells become undetectable to the immune system, making them resistant to T cell-mediated cytotoxicity[12].
Furthermore, ESCC cells actively modulate the tumor microenvironment to create an immunosuppressive state[13]. They achieve this by secreting chemokines and cytokines that recruit and activate regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)[10]. The suppressive cell populations directly inhibit the T lymphocytes (CTLs) and suppress the immune response[8].
Immune escape in ESCC also involves utilization of immune checkpoint pathways. These pathways, mediated by molecules such as PD-L1 and CTLA-4, act as a regulatory brake on the immune system to prevent excessive immune activation and autoimmunity[13,14]. ESCC cells can upregulate the expression of these checkpoint ligands, allowing them to bind to their corresponding receptors on T cells and effectively deactivate the anti-tumor T cell response[15].
In addition to the previously mentioned mechanisms, ESCC cells show a flexible immune escape repertoire. They can express ligands that bind to inhibitory receptors on T cells, leading to T cell exhaustion and dysfunction[13]. ESCC cells can also reprogram their metabolism to escape immune recognition and resist immune-mediated cytotoxicity[10]. Furthermore, they can produce immunosuppressive enzymes, such as indoleamine 2,3-dioxygenase, which reduces essential amino acids required for T cell activation and function, disabling the anti-tumor immune response[16].
By using these diverse immune escape methods, ESCC cells create a microenvironment that protects them from immune attack and promotes tumor progression. Understanding these mechanisms is crucial for developing novel therapeutic strategies that can enhance the anti-tumor immune response and improve patient outcomes.
Aryl hydrocarbon receptor (AhR) is a ubiquitous and complicated ligand-activated transcription factor that has sig
Studies have demonstrated that AhR signaling affects the proliferation and differentiation of epithelial cells, lym
AhR signaling exerts a detailed and context-specific influence on the immune system. It modulates the function of several immune cell populations, including T cells, B cells, and antigen-presenting cells (APCs)[26]. AhR activation can promote the differentiation of Tregs with immunosuppressive properties, while simultaneously inhibiting the proliferation and function of effector T cells[29]. AhR can influence the expression of MHC, and co-stimulatory molecules on APCs, and impact the efficiency of antigen presentation and T cell activation[30]. The tumor microenvironment is often characterized by chronic inflammation, which can promote tumorigenesis. AhR signaling can influence the expression of inflammatory mediators, such as cytokines and chemokines, forming an inflammatory milieu within the tumor microenvironment. While some inflammatory responses can promote anti-tumor immunity, chronic inflammation initiated by aberrant AhR activation can create a pro-tumorigenic microenvironment[27]. The multi-dimensional nature of the AhR highlights its potential as a double-edged sword. While it contributes to essential physiological processes, including xenobiotic metabolism, immune homeostasis, and tissue development, its dysregulation can be involved in various disease pathologies, including cancer. Understanding the important role of AhR signaling in ESCC, especially its influence on the tumor immune microenvironment and immune escape mechanisms, could be beneficial in the development of novel therapeutic strategies.
Exposure to environmental carcinogens, such as PAHs found in cigarette smoke and certain dietary components is a well-established risk factor for ESCC development[31]. These carcinogens can activate AhR signaling via direct ligand binding[32]. The activated AhR pathway influences multiple cellular processes that contribute to ESCC tumorigenesis. Studies have demonstrated that AhR activation can promote the proliferation of esophageal epithelial cells by modulating cell cycle regulatory proteins such as cyclin D1 and p21[33]. Moreover, AhR signaling can inhibit apoptosis and, the programmed cell death pathway, by influencing the expression of anti-apoptotic factors such as Bcl-2[34]. These effects create conditions favorable for deregulated cell proliferation, which is a characteristic of cancer. Chronic exposure to carcinogens can induce DNA damage in esophageal epithelial cells[35]. However, AhR activation can further exacerbate this issue by downregulating the expression of key DNA repair enzymes[36]. This impaired repair system increases the accumulation of mutations and, eventually increases the risk of malignant transformation. Cancer cells exhibit a distinct metabolic profile compared to healthy cells. ESCC development and progression may be initiated by a subpopulation of cancer stem cells with self-renewal and differentiation capabilities[37,38]. AhR activation has been studied in promoting the stemness properties of ESCC cells[39].
Epithelial-mesenchymal transition (EMT) is a critical process by which epithelial cells lose their polarized phenotype and acquire mesenchymal characteristics, gaining migratory and invasive potential[40]. AhR activation has been shown to induce EMT in various cell types, including esophageal epithelial cells[41]. Studies have demonstrated that AhR ligands can upregulate the expression of EMT-inducing transcription factors such as Twist1 and Snail, promoting the acquisition of an invasive phenotype by cancer cells[42]. The EMT process is crucial for ESCC progression and metastasis, by enabling cancer cells to detach from the primary tumor, migrate through the basement membrane, and invade the surrounding tissues and lymphatic vessels. EMT can also enhance the resistance of ESCC cells to anoikis, a type of cell death triggered by detachment from the extracellular matrix[43]. This combined effect of increased motility and resistance to anoikis promotes the dissemination of ESCC cells to other organs, resulting in the formation of metastases.
While certain studies have indicated that activating AhR might enhance anti-cancer immune responses, other studies suggest its possible involvement in immune evasion mechanisms in ESCC. AhR activation can suppress effector T cells, the main attacking cells of the adaptive immune response[44]. Studies have shown that some AhR ligands can inhibit the proliferation and cytokine production of CD8+ CTLs and weaken the immune response against ESCC cells[45]. Additionally, AhR activation can promote the differentiation of Tregs, a population of immunosuppressive T cells that dampens the anti-tumor immune response[46]. The tumor microenvironment in ESCC is often infiltrated by immunosuppressive myeloid cells, including MDSCs[13]. AhR activation promotes the recruitment and expansion of MDSCs, which contributes to the suppression of anti-tumor immunity[47]. Immune checkpoint molecules, such as PD-L1 and CTLA-4, act as inhibitory agents in the immune system to prevent autoimmunity. However, ESCC cells can use these checkpoints to escape immune response[48]. Some studies suggested that AhR activation upregulates the expression of PD-L1 on ESCC cells, potentially participating in immune escape by inhibiting T cell function[49]. Table 1 summarizes the influence of AhR signaling on ESCC development, progression, and immune escape.
Aspect of ESCC | Impact of AhR activation | Mechanism | Ref. |
Carcinogenesis | |||
Proliferation | Increased | Upregulates cyclin D1, downregulates p21 | [31,33] |
Apoptosis | Inhibited | Upregulates anti-apoptotic factors like Bcl-2 | [34] |
DNA repair | Impaired | Downregulates expression of key DNA repair enzymes | [36] |
Metabolic reprogramming | Promotes Warburg effect | Increases reliance on aerobic glycolysis | [28] |
Stemness | Enhanced | Promotes self-renewal and differentiation of cancer stem cells | [37,38] |
EMT | Induced | Upregulates EMT-inducing transcription factors like Twist1 and Snail | [41,43] |
Immune escape | |||
T cell function | Suppressed | Inhibits proliferation and cytokine production of CD8+ CTLs, promotes differentiation of Tregs | [45,46] |
Myeloid cell recruitment | Increased | Promotes recruitment and expansion of MDSCs | [47] |
Immune checkpoint regulation | Potential upregulation of PD-L1 expression | May contribute to immune escape by inhibiting T cell activity | [49] |
The complex influence of AhR signaling on ESCC development, progression, and immune escape presents an interesting opportunity for the development of novel therapeutic strategies. While the aberrant AhR activation can promote tumorigenesis and create an immunosuppressive microenvironment, its proper modulation could be beneficial for disrupting these processes and boosting the anti-tumor immune response.
Preclinical studies investigating AhR ligands in ESCC models have yielded in interesting results[49]. Several antagonists could competitively bind to the ligand-binding domain, and block the activation of AhR signaling pathways and their downstream effects on ESCC cells[49]. Studies have demonstrated that AhR antagonists can suppress ESCC cell proliferation, migration, and invasion, potentially inhibiting tumor progression and metastasis[50]. AhR antagonists exhibit immunomodulatory effects within the tumor microenvironment, by inhibiting AhR signaling. These antagonists may reduce the population of immunosuppressive MDSCs and Tregs, and simultaneously enhancing the function and proliferation of effector T cells, leading to a more powerful anti-tumor immune response[51,52]. Several AhR antagonists are currently under investigation for their therapeutic potential in ESCC, including CH-223191, NH3 (Ammonia), and specific small molecules[53]. Not only AhR antagonists but also some naturally derived AhR agonists, such as curcumin[54] and quercetin[55] have been shown to exhibit regulatory properties on immune response in cancer. This controversy could be due to the structural and metabolic differences of different AhR ligands. Furthermore, synthetic AhR antagonists are being actively developed, with some demonstrating promising preclinical results[51]. Table 2 has summarized some of the most promising candidates, their mechanisms of action, and potential effects on malignancies.
AhR ligands | Mechanism of action | Potential effects on malignancies | Ref. |
Natural products | |||
Curcumin | Competitive binding to the AhR ligand-binding domain | Suppresses proliferation, migration, and invasion of cancer cells; may enhance anti-tumor immunity | [54,62,63] |
Quercetin | Competitive binding to the AhR ligand-binding domain; may also inhibit AhR nuclear translocation | Suppresses proliferation and induces apoptosis in cancer cells | [55] |
Resveratrol | May interfere with AhR-DNA binding; may also possess antioxidant and anti-inflammatory properties | May inhibit tumor growth and metastasis | [55,64] |
Synthetic ligands | |||
CH-223191 | Competitive binding to the AhR ligand-binding domain | Suppresses proliferation and migration of cancer cells | [65] |
NH3 (Ammonia) | Competitive binding to the AhR ligand-binding domain | Shows promise in preclinical models, but may have limitations due to potential toxicity | [66] |
Small molecule antagonists | Competitive binding to the AhR ligand-binding domain or interfering with AhR dimerization | Several novel small molecules are under development, with preclinical studies ongoing | [67,68] |
Beyond directly targeting the AhR itself, manipulating the endogenous ligands that activate this pathway offers another potential therapeutic avenue. The gut microbiota plays an important role in metabolizing dietary components into ligands that can activate AhR signaling[56]. Strategies aimed at modulating the gut microbiota composition, potentially through prebiotics or probiotics, could be studied to influence the production of these ligands and their subsequent impact on AhR signaling in ESCC[57]. Moreover, dietary factors can also influence AhR ligand production. Identifying and employing natural AhR modulators, such as indole-3-carbinol found in cruciferous vegetables, into the diet could be a preventive or complementary therapeutic approach for ESCC patients[58,59]. Some AhR agonists such as TCDD bind tightly to the AhR, leading to long-lasting activation that disrupts normal cellular processes and promotes cancer development. However, I3C, and its metabolites transiently activate the AhR. This controlled activation helps in detoxifying carcinogens, inhibiting abnormal cell growth, and promoting cancer cell death, highlighting their potential anticancer effects[58,59]. However, the effectiveness of dietary AhR modulators is not well-established by the lack of comprehensive studies on the metabolic kinetics, permeability, and transport of dietary compounds. Future research should focus on these aspects to better understand and optimize the role of these compounds on ESCC treatment.
The therapeutic potential of AhR-targeted strategies may be further intensified when combined with existing treatment approaches for ESCC. For instance, combining selected AhR ligands (agonist or antagonist) with conventional therapies such as surgery, radiation, or chemotherapy could offer synergistic effects. These traditional therapies can induce DNA damage and cell death in ESCC cells, while AhR ligands may suppress tumor growth and metastasis by inhibiting proliferation and invasion[60]. Additionally, AhR ligands could be particularly effective when combined with immune checkpoint inhibitors[61]. Clinical trials investigating the combination of AhR-targeted therapies with other treatment strategies are suggested to determine their efficacy and safety in ESCC patients.
Immune escape mechanisms play a crucial role in ESCC progression, allowing cancer cells to evade the surveillance of the host immune system. The AhR activation, triggered by environmental carcinogens such as PAHs, promotes various hallmarks of cancer, including proliferation, apoptosis inhibition, and metabolic reprogramming. Moreover, AhR signaling contributes to immune escape by suppressing T cell function, recruiting immunosuppressive myeloid cells, and upregulating immune checkpoint molecules like PD-L1. Targeting AhR signaling presents a promising therapeutic approach for ESCC. AhR ligands (agonist or antagonist), both natural and synthetic, have shown potential in preclinical studies by inhibiting tumor growth and modulating the immune microenvironment. Modulating AhR ligands through dietary interventions may offer new therapeutic approaches. Furthermore, combining AhR-targeted therapies with conventional treatments or immune checkpoint inhibitors may result in synergistic effects, enhancing overall therapeutic efficacy.
1. | Sheikh M, Roshandel G, McCormack V, Malekzadeh R. Current Status and Future Prospects for Esophageal Cancer. Cancers (Basel). 2023;15. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 32] [Cited by in RCA: 102] [Article Influence: 51.0] [Reference Citation Analysis (0)] |
2. | Tungekar A, Mandarthi S, Mandaviya PR, Gadekar VP, Tantry A, Kotian S, Reddy J, Prabha D, Bhat S, Sahay S, Mascarenhas R, Badkillaya RR, Nagasampige MK, Yelnadu M, Pawar H, Hebbar P, Kashyap MK. ESCC ATLAS: A population wide compendium of biomarkers for Esophageal Squamous Cell Carcinoma. Sci Rep. 2018;8:12715. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 18] [Cited by in RCA: 24] [Article Influence: 3.4] [Reference Citation Analysis (0)] |
3. | Testa U, Castelli G, Pelosi E. Esophageal Cancer: Genomic and Molecular Characterization, Stem Cell Compartment and Clonal Evolution. Medicines (Basel). 2017;4. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 49] [Cited by in RCA: 61] [Article Influence: 7.6] [Reference Citation Analysis (0)] |
4. | Tarazi M, Chidambaram S, Markar SR. Risk Factors of Esophageal Squamous Cell Carcinoma beyond Alcohol and Smoking. Cancers (Basel). 2021;13. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 8] [Cited by in RCA: 21] [Article Influence: 5.3] [Reference Citation Analysis (0)] |
5. | Mandard AM, Hainaut P, Hollstein M. Genetic steps in the development of squamous cell carcinoma of the esophagus. Mutat Res. 2000;462:335-342. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 141] [Cited by in RCA: 148] [Article Influence: 5.9] [Reference Citation Analysis (0)] |
6. | Shi Y, Li MY, Wang H, Li C, Liu WY, Gao YM, Wang B, Song JW, Ma YQ. The Relationship between MACC1/c-Met/Cyclin D1 Axis Expression and Prognosis in ESCC. Anal Cell Pathol (Amst). 2022;2022:9651503. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Reference Citation Analysis (0)] |
7. | Liu WJ, Zhao Y, Chen X, Miao ML, Zhang RQ. Epigenetic modifications in esophageal cancer: An evolving biomarker. Front Genet. 2022;13:1087479. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 3] [Cited by in RCA: 5] [Article Influence: 2.5] [Reference Citation Analysis (0)] |
8. | Zheng Y, Chen Z, Han Y, Han L, Zou X, Zhou B, Hu R, Hao J, Bai S, Xiao H, Li WV, Bueker A, Ma Y, Xie G, Yang J, Chen S, Li H, Cao J, Shen L. Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment. Nat Commun. 2020;11:6268. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 69] [Cited by in RCA: 268] [Article Influence: 53.6] [Reference Citation Analysis (0)] |
9. | Tang S, Ning Q, Yang L, Mo Z, Tang S. Mechanisms of immune escape in the cancer immune cycle. Int Immunopharmacol. 2020;86:106700. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 34] [Cited by in RCA: 84] [Article Influence: 16.8] [Reference Citation Analysis (0)] |
10. | Li R, Huang B, Tian H, Sun Z. Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment. Front Oncol. 2022;12:1096717. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in RCA: 19] [Reference Citation Analysis (0)] |
11. | Zhang XJ, Yu Y, Zhao HP, Guo L, Dai K, Lv J. Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer. World J Gastroenterol. 2024;30:2195-2208. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in RCA: 3] [Reference Citation Analysis (10)] |
12. | Garrido F, Aptsiauri N. Cancer immune escape: MHC expression in primary tumours versus metastases. Immunology. 2019;158:255-266. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 85] [Cited by in RCA: 108] [Article Influence: 18.0] [Reference Citation Analysis (0)] |
13. | Baba Y, Nomoto D, Okadome K, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Baba H. Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma. Cancer Sci. 2020;111:3132-3141. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 139] [Cited by in RCA: 179] [Article Influence: 35.8] [Reference Citation Analysis (0)] |
14. | Zhang H, Dai Z, Wu W, Wang Z, Zhang N, Zhang L, Zeng WJ, Liu Z, Cheng Q. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J Exp Clin Cancer Res. 2021;40:184. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 79] [Cited by in RCA: 268] [Article Influence: 67.0] [Reference Citation Analysis (0)] |
15. | Mahmoudian RA, Mozhgani S, Abbaszadegan MR, Mokhlessi L, Montazer M, Gholamin M. Correlation between the immune checkpoints and EMT genes proposes potential prognostic and therapeutic targets in ESCC. J Mol Histol. 2021;52:597-609. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 5] [Cited by in RCA: 15] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
16. | Liu J, Lu G, Tang F, Liu Y, Cui G. Localization of indoleamine 2,3-dioxygenase in human esophageal squamous cell carcinomas. Virchows Arch. 2009;455:441-448. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 17] [Cited by in RCA: 19] [Article Influence: 1.2] [Reference Citation Analysis (0)] |
17. | Kou Z, Dai W. Aryl hydrocarbon receptor: Its roles in physiology. Biochem Pharmacol. 2021;185:114428. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 47] [Cited by in RCA: 45] [Article Influence: 11.3] [Reference Citation Analysis (0)] |
18. | Denison MS, Pandini A, Nagy SR, Baldwin EP, Bonati L. Ligand binding and activation of the Ah receptor. Chem Biol Interact. 2002;141:3-24. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 331] [Cited by in RCA: 324] [Article Influence: 14.1] [Reference Citation Analysis (0)] |
19. | Safe S, Jin UH, Park H, Chapkin RS, Jayaraman A. Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs). Int J Mol Sci. 2020;21. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in RCA: 78] [Article Influence: 15.6] [Reference Citation Analysis (0)] |
20. | Safe S, Han H, Goldsby J, Mohankumar K, Chapkin RS. Aryl Hydrocarbon Receptor (AhR) Ligands as Selective AhR Modulators: Genomic Studies. Curr Opin Toxicol. 2018;11-12:10-20. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in RCA: 51] [Article Influence: 7.3] [Reference Citation Analysis (0)] |
21. | Kerkvliet NI. AHR-mediated immunomodulation: the role of altered gene transcription. Biochem Pharmacol. 2009;77:746-760. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 123] [Cited by in RCA: 137] [Article Influence: 8.1] [Reference Citation Analysis (0)] |
22. | Yin J, Sheng B, Qiu Y, Yang K, Xiao W, Yang H. Role of AhR in positive regulation of cell proliferation and survival. Cell Prolif. 2016;49:554-560. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in RCA: 58] [Article Influence: 6.4] [Reference Citation Analysis (0)] |
23. | Li Y, Wang K, Zou QY, Jiang YZ, Zhou C, Zheng J. ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR. Reprod Toxicol. 2017;74:181-188. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 13] [Cited by in RCA: 17] [Article Influence: 2.1] [Reference Citation Analysis (0)] |
24. | Bock KW. Aryl hydrocarbon receptor (AHR) functions in NAD(+) metabolism, myelopoiesis and obesity. Biochem Pharmacol. 2019;163:128-132. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 18] [Cited by in RCA: 16] [Article Influence: 2.7] [Reference Citation Analysis (0)] |
25. | Huang Y, Zhang J, Tao Y, Ji C, Aniagu S, Jiang Y, Chen T. AHR/ROS-mediated mitochondria apoptosis contributes to benzo[a]pyrene-induced heart defects and the protective effects of resveratrol. Toxicology. 2021;462:152965. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 5] [Cited by in RCA: 44] [Article Influence: 11.0] [Reference Citation Analysis (0)] |
26. | Hao N, Whitelaw ML. The emerging roles of AhR in physiology and immunity. Biochem Pharmacol. 2013;86:561-570. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 139] [Cited by in RCA: 155] [Article Influence: 12.9] [Reference Citation Analysis (0)] |
27. | Neavin DR, Liu D, Ray B, Weinshilboum RM. The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases. Int J Mol Sci. 2018;19. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 95] [Cited by in RCA: 193] [Article Influence: 27.6] [Reference Citation Analysis (0)] |
28. | Gabriely G, Wheeler MA, Takenaka MC, Quintana FJ. Role of AHR and HIF-1α in Glioblastoma Metabolism. Trends Endocrinol Metab. 2017;28:428-436. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 64] [Cited by in RCA: 87] [Article Influence: 10.9] [Reference Citation Analysis (0)] |
29. | Liu X, Hu H, Fan H, Zuo D, Shou Z, Liao Y, Nan Z, Tang Q. The role of STAT3 and AhR in the differentiation of CD4+ T cells into Th17 and Treg cells. Medicine (Baltimore). 2017;96:e6615. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in RCA: 33] [Article Influence: 4.1] [Reference Citation Analysis (0)] |
30. | Mohammadi S, Memarian A, Sedighi S, Behnampour N, Yazdani Y. Immunoregulatory effects of indole-3-carbinol on monocyte-derived macrophages in systemic lupus erythematosus: A crucial role for aryl hydrocarbon receptor. Autoimmunity. 2018;51:199-209. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in RCA: 54] [Article Influence: 7.7] [Reference Citation Analysis (0)] |
31. | Abedi-Ardekani B, Kamangar F, Hewitt SM, Hainaut P, Sotoudeh M, Abnet CC, Taylor PR, Boffetta P, Malekzadeh R, Dawsey SM. Polycyclic aromatic hydrocarbon exposure in oesophageal tissue and risk of oesophageal squamous cell carcinoma in north-eastern Iran. Gut. 2010;59:1178-1183. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 60] [Cited by in RCA: 73] [Article Influence: 4.9] [Reference Citation Analysis (0)] |
32. | Wang Z, Snyder M, Kenison JE, Yang K, Lara B, Lydell E, Bennani K, Novikov O, Federico A, Monti S, Sherr DH. How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression. Int J Mol Sci. 2020;22. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in RCA: 63] [Article Influence: 12.6] [Reference Citation Analysis (0)] |
33. | Liu J, Min L, Zhu S, Guo Q, Li H, Zhang Z, Zhao Y, Xu C, Zhang S. Cyclin-Dependent Kinase Inhibitor 3 Promoted Cell Proliferation by Driving Cell Cycle from G1 to S Phase in Esophageal Squamous Cell Carcinoma. J Cancer. 2019;10:1915-1922. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 9] [Cited by in RCA: 14] [Article Influence: 2.3] [Reference Citation Analysis (0)] |
34. | Al-Dhfyan A, Alaiya A, Al-Mohanna F, Attwa MW, AlAsmari AF, Bakheet SA, Korashy HM. Crosstalk between aryl hydrocarbon receptor (AhR) and BCL-2 pathways suggests the use of AhR antagonist to maintain normal differentiation state of mammary epithelial cells during BCL-2 inhibition therapy. J Adv Res. 2023;50:177-192. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in RCA: 3] [Reference Citation Analysis (0)] |
35. | Bai H, Wu M, Zhang H, Tang G. Chronic polycyclic aromatic hydrocarbon exposure causes DNA damage and genomic instability in lung epithelial cells. Oncotarget. 2017;8:79034-79045. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 24] [Cited by in RCA: 32] [Article Influence: 4.0] [Reference Citation Analysis (0)] |
36. | Pollet M, Shaik S, Mescher M, Frauenstein K, Tigges J, Braun SA, Sondenheimer K, Kaveh M, Bruhs A, Meller S, Homey B, Schwarz A, Esser C, Douki T, Vogel CFA, Krutmann J, Haarmann-Stemmann T. The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis. Cell Death Differ. 2018;25:1823-1836. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 37] [Cited by in RCA: 58] [Article Influence: 8.3] [Reference Citation Analysis (0)] |
37. | Wu Q, Wu Z, Bao C, Li W, He H, Sun Y, Chen Z, Zhang H, Ning Z. Cancer stem cells in esophageal squamous cell cancer. Oncol Lett. 2019;18:5022-5032. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 2] [Cited by in RCA: 9] [Article Influence: 1.5] [Reference Citation Analysis (0)] |
38. | Khosravi A, Jafari SM, Asadi J. Knockdown of TAZ decrease the cancer stem properties of ESCC cell line YM-1 by modulation of Nanog, OCT-4 and SOX2. Gene. 2021;769:145207. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 5] [Cited by in RCA: 6] [Article Influence: 1.2] [Reference Citation Analysis (0)] |
39. | Wu C, Yu S, Tan Q, Guo P, Liu H. Role of AhR in regulating cancer stem cell-like characteristics in choriocarcinoma. Cell Cycle. 2018;17:2309-2320. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in RCA: 22] [Article Influence: 3.1] [Reference Citation Analysis (0)] |
40. | Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18:128-134. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 1104] [Cited by in RCA: 1407] [Article Influence: 201.0] [Reference Citation Analysis (0)] |
41. | Zhu P, Yu H, Zhou K, Bai Y, Qi R, Zhang S. 3,3'-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE(2) pathway. J Exp Clin Cancer Res. 2020;39:113. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 10] [Cited by in RCA: 34] [Article Influence: 6.8] [Reference Citation Analysis (0)] |
42. | Chuang KT, Chiou SS, Hsu SH. Recent Advances in Transcription Factors Biomarkers and Targeted Therapies Focusing on Epithelial-Mesenchymal Transition. Cancers (Basel). 2023;15. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in RCA: 6] [Reference Citation Analysis (0)] |
43. | Liao C, Wang Q, An J, Long Q, Wang H, Xiang M, Xiang M, Zhao Y, Liu Y, Liu J, Guan X. Partial EMT in Squamous Cell Carcinoma: A Snapshot. Int J Biol Sci. 2021;17:3036-3047. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 23] [Cited by in RCA: 31] [Article Influence: 7.8] [Reference Citation Analysis (0)] |
44. | Zhang H, Yang Z, Yuan W, Liu J, Luo X, Zhang Q, Li Y, Chen J, Zhou Y, Lv J, Zhou N, Ma J, Tang K, Huang B. Sustained AhR activity programs memory fate of early effector CD8(+) T cells. Proc Natl Acad Sci U S A. 2024;121:e2317658121. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Reference Citation Analysis (0)] |
45. | Wang G, Pan C, Cao K, Zhang J, Geng H, Wu K, Wen J, Liu C. Impacts of Cigarette Smoking on the Tumor Immune Microenvironment in Esophageal Squamous Cell Carcinoma. J Cancer. 2022;13:413-425. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 5] [Cited by in RCA: 5] [Article Influence: 1.7] [Reference Citation Analysis (0)] |
46. | Leclerc D, Staats Pires AC, Guillemin GJ, Gilot D. Detrimental activation of AhR pathway in cancer: an overview of therapeutic strategies. Curr Opin Immunol. 2021;70:15-26. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 19] [Cited by in RCA: 46] [Article Influence: 11.5] [Reference Citation Analysis (0)] |
47. | Neamah WH, Singh NP, Alghetaa H, Abdulla OA, Chatterjee S, Busbee PB, Nagarkatti M, Nagarkatti P. AhR Activation Leads to Massive Mobilization of Myeloid-Derived Suppressor Cells with Immunosuppressive Activity through Regulation of CXCR2 and MicroRNA miR-150-5p and miR-543-3p That Target Anti-Inflammatory Genes. J Immunol. 2019;203:1830-1844. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 36] [Cited by in RCA: 65] [Article Influence: 10.8] [Reference Citation Analysis (0)] |
48. | Banday AH, Abdalla M. Immune Checkpoint Inhibitors: Recent Clinical Advances and Future Prospects. Curr Med Chem. 2023;30:3215-3237. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Reference Citation Analysis (0)] |
49. | Zhu P, Zhou K, Lu S, Bai Y, Qi R, Zhang S. Modulation of aryl hydrocarbon receptor inhibits esophageal squamous cell carcinoma progression by repressing COX2/PGE2/STAT3 axis. J Cell Commun Signal. 2020;14:175-192. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 15] [Cited by in RCA: 26] [Article Influence: 5.2] [Reference Citation Analysis (0)] |
50. | To KK, Yu L, Liu S, Fu J, Cho CH. Constitutive AhR activation leads to concomitant ABCG2-mediated multidrug resistance in cisplatin-resistant esophageal carcinoma cells. Mol Carcinog. 2012;51:449-464. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 38] [Cited by in RCA: 40] [Article Influence: 2.9] [Reference Citation Analysis (0)] |
51. | Baker JR, Sakoff JA, McCluskey A. The aryl hydrocarbon receptor (AhR) as a breast cancer drug target. Med Res Rev. 2020;40:972-1001. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 27] [Cited by in RCA: 45] [Article Influence: 7.5] [Reference Citation Analysis (0)] |
52. | Sun L. Recent advances in the development of AHR antagonists in immuno-oncology. RSC Med Chem. 2021;12:902-914. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 2] [Cited by in RCA: 22] [Article Influence: 5.5] [Reference Citation Analysis (0)] |
53. | Safe S, Zhang L. The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer. Cancers (Basel). 2022;14. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in RCA: 28] [Reference Citation Analysis (0)] |
54. | Nakai R, Fukuda S, Kawase M, Yamashita Y, Ashida H. Curcumin and its derivatives inhibit 2,3,7,8,-tetrachloro-dibenzo-p-dioxin-induced expression of drug metabolizing enzymes through aryl hydrocarbon receptor-mediated pathway. Biosci Biotechnol Biochem. 2018;82:616-628. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 11] [Cited by in RCA: 11] [Article Influence: 1.4] [Reference Citation Analysis (0)] |
55. | Mohammadi-Bardbori A, Bengtsson J, Rannug U, Rannug A, Wincent E. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem Res Toxicol. 2012;25:1878-1884. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 108] [Cited by in RCA: 126] [Article Influence: 9.7] [Reference Citation Analysis (0)] |
56. | Dai G, Chen X, He Y. The Gut Microbiota Activates AhR Through the Tryptophan Metabolite Kyn to Mediate Renal Cell Carcinoma Metastasis. Front Nutr. 2021;8:712327. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 3] [Cited by in RCA: 18] [Article Influence: 4.5] [Reference Citation Analysis (0)] |
57. | Yang F, DeLuca JAA, Menon R, Garcia-Vilarato E, Callaway E, Landrock KK, Lee K, Safe SH, Chapkin RS, Allred CD, Jayaraman A. Effect of diet and intestinal AhR expression on fecal microbiome and metabolomic profiles. Microb Cell Fact. 2020;19:219. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 20] [Cited by in RCA: 19] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
58. | Peng C, Wu C, Xu X, Pan L, Lou Z, Zhao Y, Jiang H, He Z, Ruan B. Indole-3-carbinol ameliorates necroptosis and inflammation of intestinal epithelial cells in mice with ulcerative colitis by activating aryl hydrocarbon receptor. Exp Cell Res. 2021;404:112638. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 15] [Cited by in RCA: 24] [Article Influence: 6.0] [Reference Citation Analysis (0)] |
59. | Mohammadi S, Seyedhosseini FS, Behnampour N, Yazdani Y. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line. J Recept Signal Transduct Res. 2017;37:506-514. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 31] [Cited by in RCA: 28] [Article Influence: 3.5] [Reference Citation Analysis (0)] |
60. | Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H. Combination therapy in combating cancer. Oncotarget. 2017;8:38022-38043. [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited in This Article: ] [Cited by in Crossref: 890] [Cited by in RCA: 1478] [Article Influence: 211.1] [Reference Citation Analysis (0)] |
61. | Tan N, Zhao W, Wang Y, Li P, Liu J, Sun Z, Pan J, Song S, Li S, Liu Z, Bian Y. AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma. J Cancer Res Clin Oncol. 2023;149:9705-9720. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Reference Citation Analysis (0)] |
62. | Bahrami A, Majeed M, Sahebkar A. Curcumin: a potent agent to reverse epithelial-to-mesenchymal transition. Cell Oncol (Dordr). 2019;42:405-421. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 39] [Cited by in RCA: 59] [Article Influence: 9.8] [Reference Citation Analysis (0)] |
63. | Ang HL, Mohan CD, Shanmugam MK, Leong HC, Makvandi P, Rangappa KS, Bishayee A, Kumar AP, Sethi G. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Med Res Rev. 2023;43:1141-1200. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in RCA: 77] [Reference Citation Analysis (0)] |
64. | Jin Z, Feng W, Ji Y, Jin L. Resveratrol mediates cell cycle arrest and cell death in human esophageal squamous cell carcinoma by directly targeting the EGFR signaling pathway. Oncol Lett. 2017;13:347-355. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 6] [Cited by in RCA: 10] [Article Influence: 1.1] [Reference Citation Analysis (0)] |
65. | Choi EY, Lee H, Dingle RW, Kim KB, Swanson HI. Development of novel CH223191-based antagonists of the aryl hydrocarbon receptor. Mol Pharmacol. 2012;81:3-11. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 52] [Cited by in RCA: 43] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
66. | Wu H, Ma W, Wang Y, Wang Y, Sun X, Zheng Q. Gut microbiome-metabolites axis: A friend or foe to colorectal cancer progression. Biomed Pharmacother. 2024;173:116410. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Reference Citation Analysis (0)] |
67. | Kober C, Roewe J, Schmees N, Roese L, Roehn U, Bader B, Stoeckigt D, Prinz F, Gorjánácz M, Roider HG, Olesch C, Leder G, Irlbacher H, Lesche R, Lefranc J, Oezcan-Wahlbrink M, Batra AS, Elmadany N, Carretero R, Sahm K, Oezen I, Cichon F, Baumann D, Sadik A, Opitz CA, Weinmann H, Hartung IV, Kreft B, Offringa R, Platten M, Gutcher I. Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy. J Immunother Cancer. 2023;11. [PubMed] [DOI] [Full Text] [Cited in This Article: ] [Reference Citation Analysis (0)] |
68. | Joseph J, Gonzalez-lopez M, Galang C, Garcia C, Lemar H, Lu J, Vaidya K, Fischer M, Frey C, Alam M, Yao B, Dillon M, Hager JH, Venetsanakos E, Aswad F. Abstract 4719: Small-molecule antagonists of the Aryl Hydrocarbon Receptor (AhR) promote activation of human PBMCs in vitro and demonstrate significant impact on tumor growth and immune modulation in vivo. Cancer Res. 2018;78:4719-4719. [DOI] [Full Text] [Cited in This Article: ] [Cited by in Crossref: 3] [Cited by in RCA: 3] [Article Influence: 0.4] [Reference Citation Analysis (0)] |